In the galenic conversion of a pharmaceutical into a drug form, the stabilization of pharmaceuticals or adjuvants that are sensitive to hydrolysis is a matter of widespread concern. In the following, the term "hydrolysis" is understood to mean the cleavage of a substance through the effect of water. This applies, in particular, to the hydrolytic cleavage of esters, acetals, ketals, animals, and the hydrolytic cleavage of peptide pharmaceuticals.
Generally, protection against hydrolysis can be achieved by the following methods:
1. Adjusting a particular pH value, which--according to experimental findings--results in the lowest possible rate constant for the degradation of the component (1) which is sensitive to hydrolysis.
2. Forming complex bounds of the active component which is sensitive to hydrolysis by addition of suitable reactants (2) capable of complex formation. This leads to stabilisation in all those cases where the hydrolytic degradation takes place exclusively in the hydrolysis-sensitive component which is not present as a complex.
3. Decreasing the solubility of the hydrolysis-sensitive component in a medium by controlled addition of suitable substances (3, 4). Examples for this are the pH adjustment by buffer solutions and the formation of insoluble derivatives that have no propensity for solvolysis.
4. Removing water from the drug form or maintaining as far as possible an almost water-free environment of the hydrolysis-sensitive active component in a drug form (5).
All of the above-mentioned approaches 1-4 are of great importance in the pharmaceutics industry and are more or less common, depending on the form of drug. Most of these are only partially suitable for the transdermal application of pharmaceuticals by so-called transdermal therapeutic systems. The transdermal availability of a pharmaceutical is first of all dependent on its physicochemical properties. Mostly, these are negatively affected by pH changes, complexation, and by derivatisation, which is why the above-mentioned methods 1-3 are suitable only in certain cases.
The safest method is therefore to keep the active ingredient which is embedded (dissolved or dispersed) in a transdermal therapeutic system in a largely water-free environment.
The prior art known in respect of this topic can be described by two methodical approaches:
a) The production of single-dose drugs comprising a hydrolysis-sensitive pharmaceutical or adjuvant takes place under exclusion of moisture (water or water vapour) and employing primary and secondary means of packaging or packages which represent a migration barrier for the moisture present in the environment during storage and which thereby maintain the interior of the package containing the hydrolysis-sensitive component largely water-free.
b) The use of water-binding substances within the secondary package in order to bind the moisture entering the package during storage and thereby to minimise the moisture content within the primary package.
c) The use of water-binding substances within the primary package, for example by water-binding drying agents integrated in the lid of the vessel.
By contrast to most other drug forms, in transdermal therapeutic systems the primary package has an extremely large surface area. Furthermore, patch-like transdermal therapeutic systems cannot be bent or folded to keep the surface area of the package as small as possible. Thus, in such systems the primary package provides a correspondingly large boundary surface for the migration of moisture into the package. For this reason, methods a) to c) are not always sufficient to ensure the required maximum moisture content even over prolonged periods of time and under all kinds of storage conditions, and to stabilise the hydrolysis-sensitive ingredient.